Dextran sulfate is a product obtained by the sulfation of dextran and since as the free ester, it is strongly acidic and tends to decompose it is generally converted during or after production to its corresponding salt by neutralization, most often to its sodium salt.
The salts of dextran sulfate, particularly its sodium salt, have been found to be useful as an anti-coagulant, as an anti-lipemic agent, an anti-ulcer agent, and numerous other uses. Dextran sulfate has also demonstrated anti-viral activity with respect to certain viral infections such as poliomyelitis, sheep scrapie, and human immunodeficiency virus (HIV). It has most often been manufactured by sulfation of dextran with chlorsulfonic acid in pyridine, i.e. C. R. Ricketts, Biochm J. 51 210-133 (1952), by using concentrated sulfuric acid, at very low temperatures, U.S. Pat. No. 3,498,972, or by the use of chlorsulfonic acid in the presence of formamide at temperatures below 10.degree. C.. U.S. Pat. No. 3,141,014, etc.
Such methods result in products which are impure and discolored, and possibly toxic, due largely to depolymerization of dextran during the reaction, or require slow and costly procedures, or result in very low yield.
For example, the use of concentrated sulfuric acid which requires very low temperatures, is inefficient in production scale due to cooling requirements and difficulty of control since even a slight rise in temperatures may cause degradation of the dextran. Similarly, with the use of chlorsulfonic acid and pyridine, separation of the pyridine from the reaction product is carried out at a high pH which produces depolymerization of the dextran and results in an impure and discolored product, which in turn requires much further purification, and results in reduction in yield.
In the process described in U.S. Pat. No. 3,141,014 referred to above, the inventors point out the disadvantages involved in the use of pyridine as a solvent, opting instead to utilize formamide as a solvent for dextran followed by dropwise addition of chlorsulfonic acid alone or admixed with formamide. In order to achieve the proper degree of esterification and to avoid excessive polymerization of the resultant dextran sulfate the inventors carry out the greater part of the esterification reaction at temperatures in the range of 10.degree. C. and during the final stages at temperatures which can be raised to 20.degree.-35.degree. C.
Experimental procedures carried out by applicant confirmed the fact that unless temperatures were controlled in the manner set forth in U.S. Pat. No. 3,141,014, that process could not be effectively carried out to obtain products in the yields set forth. The necessity of so limiting the reaction temperatures clearly affected the yields obtainable and on the other hand were necessary in order to minimize decomposition to reactants which otherwise tended to occur.
Applicant has also found that the use of chlorsulfonic acid as a sulfating agent has the disadvantage that chlorides are formed as impurities which require removal during separation and purification procedures.